合成路线:Reduction of N-Cbz-L-phenylalaninyl chloromethyl ketone (I) with NaBH4 provided a 1:3 mixture of diastereoisomeric chlorohydrins (II) and (III),from which the required isomer (III) was isolated by recrystallization from ethyl acetate-hexane.Treatment of (III) with KOH afforded epoxide (IV),which was opened with isobutyl amine (V) in refluxing isopropanol to give amino alcohol (VI).Subsequent coupling of the amino group of (VI) with tert-butyl carbamate (VII) produced urea (VIII).Removal of the carbamate protecting group of (VIII) by hydrogenation over Pd/C and coupling of the free amine (IX) with N-Cbz-L-asparagine (X) yielded amide (XI).Further removal of the Cbz group of (XI) gave rise to amine (XII),which was finally coupled with 2-quinolinecarboxylic acid N-hydroxysuccinimidyl ester (XIII) to furnish the title quinolinecarboxamide.
合成路线:An alternative procedure for the preparation of the intermediate urea (IX) has been reported.Alkylation of L-phenylalanine (XIV) with benzyl bromide provided the N,N-dibenzyl amine (XV),which was reduced to amino alcohol (XVI) using DIBAL in cold toluene.In an improved large-scale process,amino alcohol (XVI) was prepared by benzylation of L-phenylalaninol (XVII).Swern oxidation of the alcohol function of (XVI) afforded aldehyde (XVIII).Subsequent reaction of (XVIII) with chloromethyllithium at low temperature furnished the desired epoxide (XX) along with minor amounts of its diastereoisomer (XIX).Opening of this mixture with isobutyl amine (V) gave diamino alcohol (XXIa-b).After coupling of (XXIa-b) with tert-butyl isocyanate (VII) to produce the corresponding ureas (XXIIa-b) [the required isomer (XXIIb) was isolated by recrystallization].Removal of the benzyl protecting groups of (XXIIb) then yielded the target intermediate (IX).
参考文献标题:Urea-containing hydroxyethylamine cpds.as retroviral protease inhibitors
文献作者:Talley,J.J.; Getman,D.P.; DeCrescenzo,G.A.; Lin,K.-O.; Vazquez,M.L.; Mueller,R.A.; Reed,K.L.; Heintz,R.M.; Clare,M.; Freskos,J.N.; Sun,E.T.(Pharmacia Corp.)
参考来源:JP 1995508041; WO 9323368
合成路线:Reduction of N-Cbz-L-phenylalaninyl chloromethyl ketone (I) with NaBH4 provided a 1:3 mixture of diastereoisomeric chlorohydrins (II) and (III),from which the required isomer (III) was isolated by recrystallization from ethyl acetate-hexane.Treatment of (III) with KOH afforded epoxide (IV),which was opened with isobutyl amine (V) in refluxing isopropanol to give amino alcohol (VI).Subsequent coupling of the amino group of (VI) with tert-butyl carbamate (VII) produced urea (VIII).Removal of the carbamate protecting group of (VIII) by hydrogenation over Pd/C and coupling of the free amine (IX) with N-Cbz-L-asparagine (X) yielded amide (XI).Further removal of the Cbz group of (XI) gave rise to amine (XII),which was finally coupled with 2-quinolinecarboxylic acid N-hydroxysuccinimidyl ester (XIII) to furnish the title quinolinecarboxamide.
合成路线:An alternative procedure for the preparation of the intermediate urea (IX) has been reported.Alkylation of L-phenylalanine (XIV) with benzyl bromide provided the N,N-dibenzyl amine (XV),which was reduced to amino alcohol (XVI) using DIBAL in cold toluene.In an improved large-scale process,amino alcohol (XVI) was prepared by benzylation of L-phenylalaninol (XVII).Swern oxidation of the alcohol function of (XVI) afforded aldehyde (XVIII).Subsequent reaction of (XVIII) with chloromethyllithium at low temperature furnished the desired epoxide (XX) along with minor amounts of its diastereoisomer (XIX).Opening of this mixture with isobutyl amine (V) gave diamino alcohol (XXIa-b).After coupling of (XXIa-b) with tert-butyl isocyanate (VII) to produce the corresponding ureas (XXIIa-b) [the required isomer (XXIIb) was isolated by recrystallization].Removal of the benzyl protecting groups of (XXIIb) then yielded the target intermediate (IX).
参考文献标题:Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere
文献作者:Getman,D.P.; DeCrescenzo,G.A.; Heintz,R.M.; Reed,K.L.; Talley,J.J.; Bryant,M.L.; Clare,M.; Houseman,K.A.; Marr,J.J.; Mueller,R.A.; et al.
参考来源:J Med Chem 1993,36(2),288
合成路线:An alternative procedure for the preparation of the intermediate urea (IX) has been reported.Alkylation of L-phenylalanine (XIV) with benzyl bromide provided the N,N-dibenzyl amine (XV),which was reduced to amino alcohol (XVI) using DIBAL in cold toluene.In an improved large-scale process,amino alcohol (XVI) was prepared by benzylation of L-phenylalaninol (XVII).Swern oxidation of the alcohol function of (XVI) afforded aldehyde (XVIII).Subsequent reaction of (XVIII) with chloromethyllithium at low temperature furnished the desired epoxide (XX) along with minor amounts of its diastereoisomer (XIX).Opening of this mixture with isobutyl amine (V) gave diamino alcohol (XXIa-b).After coupling of (XXIa-b) with tert-butyl isocyanate (VII) to produce the corresponding ureas (XXIIa-b) [the required isomer (XXIIb) was isolated by recrystallization].Removal of the benzyl protecting groups of (XXIIb) then yielded the target intermediate (IX).
参考文献标题:Development of large-scale process for an HIV protease inhibitor
文献作者:Liu,C.; et al.
参考来源:Org Process Res Dev 1997,1(1),45
产品链接: CAS No. 143224-34-4››